Medicine:Blue cone monochromacy

From HandWiki
Revision as of 21:14, 5 March 2023 by Carolyn (talk | contribs) (simplify)
(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)
Blue cone monochromacy
SpecialtyOphthalmology

Blue cone monochromacy (BCM) is an inherited eye disease that causes severely impaired color discrimination, low vision, nystagmus and photophobia[1][2][3][4][5][6][7][8] due to the absence of functionality of red (L) and green (M) cone photoreceptor cells in the retina.[9][1] This form of retinal disorder is a recessive X-linked disease[10][11][12] and manifests its symptoms in early infancy.[1][13][5]

Blue cone monochromacy is considered a stationary (non-progressive) disease, although there is evidence of disease progression with macular degeneration in many patients.[14][7]

Symptoms

Cone photoreceptor cells[15] in the retina are responsible for color vision,[16][17][18][19][20] and are categorized as L, M, and S which refer to the wavelengths of light each is sensitive to. L (long) is most sensitive to red, M (medium) to green, and S (short) to blue. L-cones and M-cones are most responsible for visual acuity as they are concentrated in the fovea centralis, the central visual field. Blue cone monochromacy is a severe condition in which the cones sensitive to red or green light are missing or defective, and only S-cones sensitive to blue light and rods which are responsible for night (scotopic) vision are functional.[9][1]

A variety of symptoms characterize BCM:[1][4][2][3][7][13][8][5] affected individuals have low vision with a visual acuity between 20/60 and 20/200, and poor color discrimination. Phenomena such as photophobia (hemeralopia), which describes the event in which light is perceived as an intense glare, often manifest. Moreover, nystagmus[2] is present from the age of 2 months though it may slowly decrease with age.[4] Families with BCM-affected individuals show a recessive X-linked inheritance pattern.[11][21][22][10]

The majority of subjects with BCM are thought to have a stable condition, although there are cases showing evidence of disease progression and macular changes.[14][7][8]

Genetics

Blue cone monochromacy is inherited from the X chromosome.[12][11][21][22][10]

The genes involved in the BCM are on chromosome X, at position Xq28,[21] at the end of the q arm of the X chromosome. The genes’ names are:

Type OMIM Gene Locus
Locus Control Region Online Mendelian Inheritance in Man (OMIM) 303700 LCR][9][1][12] Xq28
opsin Online Mendelian Inheritance in Man (OMIM) 303700 OPN1LW][9][1][12] Xq28
opsin Online Mendelian Inheritance in Man (OMIM) 303700 OPN1MW][9][1][12] Xq28

LCR is the Locus Control Region, and acts as a promoter of the expression of the two opsin genes thereafter.[9][23] In the absence of this gene, none of the following two opsin genes are expressed in the human retina.[11][23] In addition, it ensures that only one of the two opsin genes (red or green) is expressed exclusively in each cone.[23][24] OPN1LW[25] and OPN1MW [26] are respectively the genes that contain the genetic code for protein opsin needed for the cone pigments which select red or green light.[16][18]

The gene responsible for the formation of the blue photopigment is in a position far away, on chromosome 7[16] and the gene responsible for the formation of rhodopsin (the rod photopigment) is located on chromosome 3.

There are many genetic mutations that can affect this group of genes, LCR, OPN1LW and OPN1MW[9][1][27][24][28] that lead to the BCM: a deletion of the LCR[9] ,[1][23] intragenic deletion of exons within the genes OPN1LW and OPN1MW[29] and a 2 steps mechanism with an homologous recombination and a punctual inactivation.[1][27]

The point mutation is the so-called C203R. The name of the point mutations indicates the position at which mutation has occurred, in this case the amino acid position 203 and which has been replaced, in this case a C = Cysteine with an R = Arginine. The C203R mutation causes the opsin protein once formed does not carry the folding,[30] that is it doesn't take the proper three-dimensional form. Other point mutations are the P307L[31] and R247X.[29] The last one replaces arginine with the Stop codon, prematurely stopping at position 247 the formation of the protein (nonsense mutation). Other mutations on genes OPN1LW and OPN1MW that lead to the blue cone monochromacy are constituted by a set of point mutations called for example LIAVA.[24][28] Blue cone monochromacy will be caused by the production of new hybrid gene, like in the previous case, from the homologous recombination of OPN1LW and OPN1MW. Exon 3 of the hybrid gene contains the following amino acids in the positions indicated: 153 Leucine, 171 Isoleucine, 174 Alanine, 178 Valine and 180 Alanine. This genotype has the abbreviated name LIAVA.[24]

Another disease of the retina that is associated with the position Xq28 is Bornholm Eye Disease (BED).[24]

Finally note there is also a particular mutation of the two genes OPN1LW and OPN1MW which causes a different disease from the blue cone monochromacy. This type of mutation is named W177R and is a misfolding mutation that, if present on both opsin genes cause cone dystrophy with evidence of degeneration and cell death of the cones.[13]

Diagnosis

In a male child, from 2 months upwards, an aversion to light and nystagmus[4] may lead to the suspicion of a case of blue cone monochromacy, but it does not provide sufficient indications to establish the form of the condition. To identify a case of BCM, it is necessary to reconstruct the family history,[11][12] with the condition linked to the transmission of the X chromosome if there are other cases in the family.[1][14][5][7][28][8]

The electroretinogram (ERG), can demonstrate the loss of cone function with retained rod function.[32][2][3]

In adult individuals a color test like a Farnsworth D-15,[7] a Farnsworth Munsell 100 Hue test[2] can be part of the diagnosis tools and a Berson test[33][34] makes it possible to distinguish blue cone monochromacy from other diseases. Visual acuity is usually tested in adults and is between 20/60 and 20/200.[5]

Treatment

There is no cure for blue cone monochromacy; however, the efficacy and safety of various prospective treatments are currently being evaluated. Gene therapy is actually the most promising one.[5][35] The goal of gene therapy[36] studies is to virally supplement retinal cells expressing mutant genes associated with the blue cone monochromacy phenotype with healthy forms of the gene; thus, allowing the repair and proper functioning of retinal photoreceptor cells in response to the instructions associated with the inserted healthy gene.

Corrective visual aides and personalized vision therapy provided by Low Vision Specialists may help patients correct glare and optimize their remaining visual acuity. Tinted lenses for photophobia allow for greater visual comfort. A magenta (mixture of red and blue) tint allows for best visual acuity since it protects the rods from saturation while allowing the blue cones to be maximally stimulated.

Epidemiology

BCM is a cause of inherited low vision[5][35] with approximately 1/100,000 individuals experiencing the disease within their lifetime.[12][6] The disease affects male recipients of the X-linked mutation, while females usually remain unaffected carriers of the BCM trait.[11][21] [22]

History

Prior to the 1960s, blue cone monochromacy was not distinguishable from achromatopsia. The first detailed description of achromatopsia is that given by Huddart (1777).[37] The subject of that report 'could never do more than guess the name of any color; yet he could distinguish white from black, or black from any light or bright color...He had 2 brothers in the same circumstances as to sight; and 2 brothers and sisters who, as well as his parents, had nothing of this defect.' Sloan in 1954 studied several patients affected by BCM.[38] Blackwell and Blackwell (1961)[39] described patients who can distinguish blue and yellow signals and seems to have functional rods and S-cones cells. Studies of this time showed that blue cone monochromacy was distinct from complete achromatopsia (rod monochromacy), at least hereditarily, and became briefly known as x-linked achromatopsia. Information presented by Spivey (1965)[10] indicated that affected persons can see small blue objects on a large yellow field and vice versa. The disease has been studied also by Alpern et al. (1960)[4] and by Fleischman in 1981.[40] The most important results have been obtained in 1989 and 1993 by Nathans et al.[9][1] and by Reyniers et al. in 1991[27] who identified the genes causing blue cone monochromacy.

Following previous important works several research groups worked on blue cone monochromacy with the aim to describe genotype and phenotype features of the disease.[41][2][14][3][6][7][8][28]

High-resolution imaging of the cone mosaic in the living human eye using Adaptive Optics has made it possible to address the question of how different genetic rearrangements affect the retinal phenotype at the cellular level. Cone Mosaic studies performed with Adaptive Optics technology revealed a disruption of the normal pattern of photoreceptors human cone mosaic in presence of the most frequent causative BCM genetic mutations. Adaptive optics images show that the number of visible cones was significantly reduced and the regularity of the cone mosaic was disrupted compared to normals. These imaging data suggest that failure to express opsin results in the early degeneration of the associated cone photoreceptor.[42][43][44][45]

Blue cone monochromacy has been studied with the aim to find a treatment.[5][35]

Research

Future treatments may involve gene therapy.[5][35] In fact it seems that in case of a genetic deletion of the human cone visual pigment there is a sufficient number of photoreceptors to warrant Gene Therapy. In 2015 scientists at the University of Pennsylvania evaluated possible outcoming measures of BCM gene therapy[35]

A previous important result shows that in adult primates it is possible to restore colour vision through an AAV gene therapy that introduced a new opsin in the primate retina.[46] A mouse model of blue cone monochromacy has been treated with gene-based therapy.[36]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 Nathans, J; Maumenee, I H; Zrenner, E; Sadowski, B; Sharpe, L T; Lewis, R A; Hansen, E; Rosenberg, T et al. (1993). "Genetic heterogeneity among blue-cone monochromats". Am. J. Hum. Genet. 53 (5): 987–1000. PMID 8213841. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Ayyagari, R; Kakuk, L E; Bingham, E L; Szczesny, J J; Kemp, J; Toda, Y; Felius, J; Sieving, P A (2000). "Spectrum of color gene deletions and phenotype in patients with blue cone monochromacy". Hum. Genet. 107 (1): 75–82. doi:10.1007/s004390000338. PMID 10982039. https://deepblue.lib.umich.edu/bitstream/2027.42/42266/1/439-107-1-75_s004390000338.pdf. 
  3. ↑ 3.0 3.1 3.2 3.3 Mizrahi-Meissonnier, L; Merin, S; Banin, E; Sharon, D (2010). "Variable Retinal Phenotypes caused by mutations in the X-linked phopigment gene array". Investigative Ophthalmology & Visual Science 51 (8): 3884–92. doi:10.1167/iovs.09-4592. PMID 20220053. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Alpern, M; Falls, H F; Lee, G B (1960). "The enigma of typical total monochromacy". Am. J. Ophthalmol. 50 (5): 996–1012. doi:10.1016/0002-9394(60)90353-6. PMID 13682677. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 Cideciyan, A V; Hufnagel, R B; Carroll, J; Sumaroka, A; Luo, X; Schwartz, S B; Dubra, A; Land, M et al. (2013). "Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapy". Hum. Gene Ther. 24 (12): 993–1006. doi:10.1089/hum.2013.153. PMID 24067079. 
  6. ↑ 6.0 6.1 6.2 Gardner, J C; Michaelides, M; Holder, G E; Kanuga, N; Webb, T R; Mollon, J D; Moore, A T; Hardcastle, A J (2009). "Blue cone monochromacy: causative mutations and associated phenotypes". Mol. Vis. 15: 876–884. PMID 19421413. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 Michaelides, M; Johnson, S; Simunovic, M P; Bradshaw, K; Holder, G; Mollon, J D; Moore, A T; Hunt, D M (2005). "Blue cone monochromatism: a phenotype and genotype assessment with evidence of progressive loss of cone function in older individuals". Eye (Lond) 19 (1): 2–10. doi:10.1038/sj.eye.6701391. PMID 15094734. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 Keller, U; Wissinger, B; Tippmann, S; Kohl, S; Kraus, H; Foerster, M H (2004). "Blue cone monochromatism: clinical findings in patients with mutations in the red/green opsin gene cluster". Graefes Arch. Clin. Exp. Ophthalmol. 242 (9): 729–735. doi:10.1007/s00417-004-0921-z. PMID 15069569. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 Nathans, J; Davenport, C M; Maumenee, I H; Lewis, R A; Hejtmancik, J F; Litt, M; Lovrien, E; Weleber, R et al. (1989). "Molecular genetics of human blue cone monochromacy". Science 245 (4920): 831–838. doi:10.1126/science.2788922. PMID 2788922. Bibcode: 1989Sci...245..831N. 
  10. ↑ 10.0 10.1 10.2 10.3 Spivey, B E (1965). "The X-linked recessive inheritance of atypical monochromatism". Arch. Ophthalmol. 74 (3): 327–333. doi:10.1001/archopht.1965.00970040329007. PMID 14338644. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 Lewis, R A; Holcomb, J D; Bromley, W C; Wilson, M C; Roderick, T H; Hejtmancik, J F (1987). "Mapping X-linked ophthalmic diseases: III. Provisional assignment of the locus for Blue Cone Monochromacy to Xq28". Arch. Ophthalmol. 105 (8): 1055–1059. doi:10.1001/archopht.1987.01060080057028. PMID 2888453. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 Kohl, S; Hamel, C P (2011). "Clinical utility gene card for: blue cone monochromatism". Eur. J. Hum. Genet. 19 (6): 732. doi:10.1038/ejhg.2010.232. PMID 21267011. 
  13. ↑ 13.0 13.1 13.2 Gardner, J C; Webb, T R; Kanuga, N; Robson, A G; Holder, G E; Stockman, A; Ripamonti, C; Ebenezer, N D et al. (2010). "X-Linked Cone Dystrophy Caused by Mutation of the Red and Green Cone Opsins". Am. J. Hum. Genet. 87 (1): 26–39. doi:10.1016/j.ajhg.2010.05.019. PMID 20579627. 
  14. ↑ 14.0 14.1 14.2 14.3 Ayyagari, R; Kakuk, L E; Coats, C L; Bingham, E L; Toda, Y; Felius, J; Sieving, P A (1999). "Bilateral macular atrophy in blue cone monochromacy (BCM) with loss of the locus control region (LCR) and part of the red pigment gene". Mol. Vis. 28: 5–13. PMID 10427103. 
  15. ↑ "Structure of cone photoreceptors". Prog Retin Eye Res 28 (4): 289–302. July 2009. doi:10.1016/j.preteyeres.2009.05.003. PMID 19501669. 
  16. ↑ 16.0 16.1 16.2 Nathans, J; Thomas, D; Hogness, D S (1986). "Molecular genetics of human color vision: the genes encoding blue, green, and red pigments". Science 232 (4747): 193–202. doi:10.1126/science.2937147. PMID 2937147. Bibcode: 1986Sci...232..193N. 
  17. ↑ Nathans, J; Piantanida, T P; Eddy, R L; Shows, T B; Hogness, D S (1986). "Molecular genetics of inherited variation in human color vision". Science 232 (4747): 203–210. doi:10.1126/science.3485310. PMID 3485310. Bibcode: 1986Sci...232..203N. 
  18. ↑ 18.0 18.1 Nathans, J (1987). "Molecular biology of visual pigments". Annu. Rev. Neurosci. 10: 163–194. doi:10.1146/annurev.ne.10.030187.001115. PMID 3551758. 
  19. ↑ Nathans, J (1999). "The evolution and physiology of human color vision: insights from molecular genetic studies of visual pigments". Neuron 24 (2): 299–312. doi:10.1016/s0896-6273(00)80845-4. PMID 10571225. 
  20. ↑ Deeb, S S (2005). "The molecular basis of variation in human color vision". Clin. Genet. 67 (5): 369–377. doi:10.1111/j.1399-0004.2004.00343.x. PMID 15811001. 
  21. ↑ 21.0 21.1 21.2 21.3 "Colour vision in blue-cone 'monochromacy'". J. Physiol. 212 (1): 211–33. January 1971. doi:10.1113/jphysiol.1971.sp009318. PMID 5313219. 
  22. ↑ 22.0 22.1 22.2 Crognale, M A; Fry, M; Highsmith, J; Haegerstrom-Portnoy, G; Neitz, M; Neitz, J; Webster, M A (2004). "Characterization of a novel form of X-linked incomplete achromatopsia". Vis. Neurosci. 21 (3): 197–203. doi:10.1017/s0952523804213384. PMID 15518189. 
  23. ↑ 23.0 23.1 23.2 23.3 Wang, Y; Macke, J P; Merbs, S L; Zack, D J; Klaunberg, B; Bennett, J; Gearhart, J; Nathans, J (1992). "A locus control region adjacent to the human red and green visual pigment genes". Neuron 9 (3): 429–440. doi:10.1016/0896-6273(92)90181-c. PMID 1524826. 
  24. ↑ 24.0 24.1 24.2 24.3 24.4 Neitz, J; Neitz, M (2011). "The genetics of normal and defective color vision". Vision Res. 51 (7): 633–651. doi:10.1016/j.visres.2010.12.002. PMID 21167193. 
  25. ↑ OPN!LW Opsin gene. "Opsin LW gene". http://ghr.nlm.nih.gov/gene/OPN1LW. 
  26. ↑ Opsin Gene. "OPN1MW Opsin Gene". http://ghr.nlm.nih.gov/gene/OPN1MW. 
  27. ↑ 27.0 27.1 27.2 Reyniers, E; Van Thienen, M N; Meire, F; De Boulle, K; Devries, K; Kestelijn, P; Willems, P J (1995). "Gene conversion between red and defective green opsin gene in blue cone monochromacy". Genomics 29 (2): 323–328. doi:10.1006/geno.1995.9998. PMID 8666378. 
  28. ↑ 28.0 28.1 28.2 28.3 Gardner, J C; Liew, G; Quan, Y H; Ermetal, B; Ueyama, H; Davidson, A E; Schwarz, N; Kanuga, N et al. (2014). "A three different cone opsin gene array mutational mechanisms with genotype–phenotype correlation and functional investigation of cone opsin variants". Hum. Mutat. 35 (11): 1354–1362. doi:10.1002/humu.22679. PMID 25168334. 
  29. ↑ 29.0 29.1 "Defective colour vision associated with a missense mutation in the human green visual pigment gene". Nat. Genet. 1 (4): 251–6. July 1992. doi:10.1038/ng0792-251. PMID 1302020. 
  30. ↑ Kazmi, M A; Sakmar, T P; Ostrer, H (1997). "Mutation of a conserved cysteine in the X-linked cone opsins causes color vision deficiencies by disrupting protein folding and stability". Invest. Ophthalmol. Vis. Sci. 38 (6): 1074–1081. PMID 9152227. 
  31. ↑ Ladekjaer-Mikkelsen, A S; Rosenberg, T; Jørgensen, A L (1996). "A new mechanism in blue cone monochromatism". Hum. Genet. 98 (4): 403–408. doi:10.1007/s004390050229. PMID 8792812. 
  32. ↑ Andréasson, S; Tornqvist, K (1991). "Electroretinograms in patients with achromatopsia". Acta Ophthalmol (Copenh) 69 (6): 711–716. doi:10.1111/j.1755-3768.1991.tb02048.x. PMID 1789084. 
  33. ↑ "Color plates to help identify patients with blue cone monochromatism". Am. J. Ophthalmol. 95 (6): 741–7. June 1983. doi:10.1016/0002-9394(83)90058-2. PMID 6602551. 
  34. ↑ Pinckers, A (1992). "Berson test for blue cone monochromatism". Int. Ophthalmol. 16 (3): 185–186. doi:10.1007/bf00916439. PMID 1452423. 
  35. ↑ 35.0 35.1 35.2 35.3 35.4 Luo, X; Cideciyan, AV; Iannaccone, A; Roman, A J; Ditta, L C; Jennings, B J; Yatsenko, S; Sheplock, R et al. (2015). "Blue Cone Monochromacy: visual function and efficacy outcome measures for clinical trials". PLOS ONE 10 (4): e0125700. doi:10.1371/journal.pone.0125700. PMID 25909963. Bibcode: 2015PLoSO..1025700L. 
  36. ↑ 36.0 36.1 Zhang, Y; Deng, WT; Du, W; Zhu, P; Li, J; Xu, F; Sun, J; Gerstner, C D et al. (2017). "Gene-based Therapy in a Mouse Model of Blue Cone Monochromacy". Scientific Reports 7 (6690): 6690. doi:10.1038/s41598-017-06982-7. PMID 28751656. Bibcode: 2017NatSR...7.6690Z. 
  37. ↑ Huddart, J (1777). "An account of persons who could not distinguish colours". Philos. Trans. R. Soc. 67: 260. doi:10.1098/rstl.1777.0015. 
  38. ↑ "Congenital achromatopsia; a report of 19 cases". J Opt Soc Am 44 (2): 117–28. February 1954. doi:10.1364/josa.44.000117. PMID 13131176. Bibcode: 1954JOSA...44..117S. 
  39. ↑ Blackwell, H R; Blackwell, O M (1961). "Rod and cone receptor mechanisms in typical and atypical congenital achromatopsia". Vision Res. 1 (1–2): 62–107. doi:10.1016/0042-6989(61)90022-0. 
  40. ↑ Fleischman, J A; O'Donnell, F E (1981). "Congenital X-linked incomplete achromatopsia. Evidence for slow progression, carrier fundus findings, and possible genetic linkage with glucose-6-phosphate dehydrogenase locus". Arch. Ophthalmol. 99 (3): 468–472. doi:10.1001/archopht.1981.03930010470016. PMID 6971088. 
  41. ↑ Reitner, A; Sharpe, L T; Zrenner, E (1991). "Is colour vision possible with only rods and blue-sensitive cones?". Nature 352 (6338): 798–800. doi:10.1038/352798a0. PMID 1881435. Bibcode: 1991Natur.352..798R. 
  42. ↑ Carroll, J; Neitz, M; Hofer, H; Neitz, J; Williams, D R (2004). "Functional photoreceptor loss revealed with adaptive optics: an alternate cause of color blindness". Proc. Natl. Acad. Sci. USA 101 (22): 8461–8466. doi:10.1073/pnas.0401440101. PMID 15148406. Bibcode: 2004PNAS..101.8461C. 
  43. ↑ Carroll, J; Rossi, E A; Porter, J; Neitz, J; Roorda, A; Williams, D R; Neitz, M (2010). "Deletion of the X-linked opsin gene array locus control region (LCR) results in disruption of the cone mosaic". Vision Res. 50 (19): 1989–1999. doi:10.1016/j.visres.2010.07.009. PMID 20638402. 
  44. ↑ Carroll, J; Baraas, R C; Wagner-Schuman, M; Rha, J; Siebe, C A; Sloan, C; Tait, D M; Thompson, S et al. (2009). "Cone photoreceptor mosaic disruption associated with Cys203Arg mutation in the M-cone opsin". Proc. Natl. Acad. Sci. USA 106 (49): 20948–20953. doi:10.1073/pnas.0910128106. PMID 19934058. Bibcode: 2009PNAS..10620948C. 
  45. ↑ Wagner-Schuman, M; Neitz, J; Rha, J; Williams, D R; Neitz, M; Carroll, J (2010). "Color-deficient cone mosaics associated with Xq28 opsin mutations: A stop codon versus gene deletions". Vision Res. 50 (23): 2396–2402. doi:10.1016/j.visres.2010.09.015. PMID 20854834. 
  46. ↑ Mancuso, K; Hauswirth, W W; Li, Q; Connor, T B; Kuchenbecker, J A; Mauck, M C; Neitz, J; Neitz, M (2009). "Gene therapy for red-green colour blindness in adult primates". Nature 461 (7265): 784–787. doi:10.1038/nature08401. PMID 19759534. Bibcode: 2009Natur.461..784M. 

External links




Retrieved from "https://handwiki.org/wiki/index.php?title=Medicine:Blue_cone_monochromacy&oldid=2557085"